1. Field of the Invention
The present invention relates generally to the field of steroids, and in particular, to 17.alpha.-(substituted-methyl) steroids represented by partial formula (II), wherein Z is selected from residues represented by partial formulas (III) and (IV), which structures possess a variety of valuable biological properties including glucocorticoid and anti-glucocorticoid, progestational and anti-progestational activities. The invention is also directed to pharmaceutical compositions containing the steroids disclosed in this invention.
2. Description of the Background Art
M. Hubner, K. Ponsold, M. Oettel and R. Freund, [Arzneim.-Forsch, Drug Res. 30:401-406 (1980)] described the preparation of 17.beta.-hydroxy-17.alpha.-(substituted-methyl) derivatives of estra-4,9-dien- 3-one (I; R=H, R.sup.1 =Me) and gona-4,9-dien-3-one (I; R=Me, R.sup.1 =Et) in which the substituents were:
R.sup.1 =Me; X=N.sub.3, CN, Br, Cl PA0 R.sup.1 =Et; X=N.sub.3. PA0 17.alpha.-Cyanomethyl- (II; X=CN), PA0 17.alpha.-Azidomethyl- (II; X=N.sub.3), PA0 17.alpha.-Thiocyanomethyl (II; X=SCN), PA0 17.alpha.-Methoxymethyl (II; X=OMe), and PA0 17.alpha.-Phenylmethyl(benzyl) (II; X=Ph) PA0 17.alpha.-Ethynylmethyl (II; X=CH.sub.2 C.tbd.CH) PA0 R is H, acyl (C.sub.1 -C.sub.10), lower alkyl (C.sub.1 -C.sub.3); PA0 R.sub.1 is methyl or ethyl; PA0 R.sup.3 is H or methyl; and PA0 R.sup.2 is selected from the group consisting of oxo, 11.alpha.-hydrogen, 11.beta.- PA0 --OH, except when X=CN and R is H PA0 -lower alkyl (C.sub.1 -C.sub.10); PA0 -lower alkenyl (C.sub.1 -C.sub.10), with the understanding that when C=1, the alkenyl group is methylene and is attached directly to position C.sub.11 ; PA0 -lower alkynyl (C.sub.1 -C.sub.10); PA0 --C.sub.6 H.sub.5 and --C.sub.6 H.sub.4.R.sup.4 ; PA0 --(CH.sub.2)n.R.sup.5 wherein n is 1 to 4; PA0 -pyridyl; PA0 -thiazolyl; PA0 -piperidinyl; PA0 --O-lower alkyl (C.sub.1 -C.sub.3); PA0 -halogen; PA0 --CF.sub.3 ; PA0 --C.sub.6 H.sub.5 ; PA0 --S-lower alkyl or -phenyl; and PA0 R.sup.5 is selected from the group consisting of--NMe.sub.2,--NEt.sub.2, ##STR3## OMe. PA0 R is H or lower acyl and in particular acetyl, propionyl, and butyryl; PA0 R.sup.1 is methyl; PA0 R.sup.2 is .alpha.-H, .beta.-OH (except where X=CN) or .dbd.O; and PA0 R.sup.3 is H. PA0 R is H or lower acyl and in particular acetyl, propionyl, and butyryl; PA0 R.sup.1 is methyl or ethyl; and PA0 R.sup.2 is .alpha.-H and an 11.beta.-substituent as hereinabove defined containing N or S in the molecule except when X=--C.tbd.CH. Preferred substituents are selected from the group consisting of: ##STR4## PA0 R is H or lower acyl and in particular acetyl, propionyl, and butyryl; PA0 R.sup.1 is methyl or ethyl; PA0 R.sup.2 is .alpha.-H and .beta. is lower alkyl such as, for example, methyl, ethyl, and n-propyl; PA0 R.sup.2 is .alpha.-H and .beta. is lower alkenyl such as, for example, methylene, vinyl, propenyl, allyl, and isopropenyl; PA0 R.sup.2 is .alpha.-H and .beta. is aryl such as, for example, phenyl, p-methoxyphenyl, p-fluorophenyl, and trifluoromethylphenyl; PA0 R.sup.2 is .alpha.-H, .beta.-thienyl; PA0 R.sup.2 is .alpha.-H, .beta.-trifluoromethyl; and PA0 R.sup.3 is H or methyl. PA0 R is H or lower acyl and in particular acetyl, propionyl and butyryl; PA0 R.sup.1 is methyl or ethyl; PA0 R.sup.2 is .alpha.-H and an 11.beta. substituent as hereinabove defined containing N or S in the molecule except when X=--C.tbd.CH. Preferred substituents are selected from the group consisting of: ##STR5##
These structures were characterized as progestational agents. In particular, when R=H, R.sup.1 =Me and X=CN, the steroid designated STS 557 was obtained which had ten times the oral potency of levonorgestrel as a gestagen (M. Hubner and K. Ponsold, Exper. Clin. Endocrinol. 81:109-114 [1983]). Incubation of STS 557 with female rat liver microsomes led to isolaion, inter alia, of the metabolite 17.alpha.-cyanomethyl-11.beta.,17.beta.-dihydroxyestra-4,9-dien-3-one (II; R=H, R.sup.1 =Me, R.sup.2 =.alpha.-H,.beta.-OH, Z=III, R.sup.3 =H) but no biological activity was reported for this product (Exper. Clin. Endocrinol. 81: 168-174 [1983]). This product is excluded from the claims of this invention.
In Eur. Pat. Appln. E.P.129,499 (1984), G. Neef, G. Sauer, R. Wiechert, S. Beie, D. Henderson and R. Rohde describe steroids of type (V) wherein the substituted-methyl group at C17 is introduced via 17-oxo intermediates. The compounds of that invention are characterized by a 13.alpha.-methyl substituent and thus fall outside the present claims which require a 13.beta. substituent.
In U.S. Pat. No. 4,447,424 to J. G. Teutsch, D. Philibert and R. Deraedt are disclosed steroids of structure (II) wherein the substituents are as follows:
______________________________________ R R.sup.1 R.sup.2 [.alpha.-H,.beta.= X ______________________________________ H Me .C.sub.6 H.sub.4 s(CH.sub.2).sub.2 N&lt; CN H Me .C.sub.6 H.sub.4 --N&lt; CH.sub.2 C.tbd.CH H Me .C.sub.6 H.sub.4 C.sub.6 H.sub.4 --N&lt; CH.sub.2 C.tbd.CH H Me .C.sub.6 H.sub.4 OCH.sub.2 CH.sub.2 N&lt; CH.sub.2 C.tbd.CH H Me .C.sub.6 H.sub.4 SCH.sub.2 CH.sub.2 N&lt; CH.sub.2 C.tbd.CH H Me .C.sub.10 H.sub.6 N&lt; CH.sub.2 C.tbd.CH ______________________________________
and Z=(III); where R.sup.3 =H. These structures are claimed to have anti-glucocorticoid properties. They are excluded from the claims of the present invention.
U.S. Pat. No. 3,906,096 to Bucourt et al is directed to steroidal compounds which have anti-androgenic and anti-estrogenic activities. The compounds of Bucourt et al are different from the present compounds in that the former have an alkoxy group at the 11 position. Further, the compounds of Bucourt et al do not include the .DELTA..sup.4,9 series of compounds as in this invention, nor does the reference disclose a 17.alpha. substituent containing a hetero atom.
U.S. Pat. No. 4,540,686 to Philibert et al discloses compounds having anti-glucocorticoid activity. This reference does not disclose 17.alpha. substituents containing a hetero atom such as azidomethyl or methoxymethyl.
U.S. Pat. No. 4,547,493 to Teutsch et al is directed to steroidal compounds which have anti-glucocorticoid activity. The .DELTA..sup.4,9 steroids of Teutsch et al require a substituent other than hydrogen at the 2 position of the steroid ring system, and therefore the compounds of the reference fall outside of the scope of the present claims.
U.S. Pat. No. 4,233,296 to Teutsch et al is directed to 11.beta.-substituted-.DELTA..sup.4,9 -estradienes having progestomimetic activity. The only 17.beta. substituted methyl substituent is a 2-propynyl group.
Although a large group of steroidal compounds with biological activity is known, as evidenced by the above-described disclosures, there remains a need to discover new and more effective steroidal compounds possessing biological activity, particularly glucocorticoid/anti-glucocorticoid or progestational/anti-progestational activity.